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Aberrant methylation of WD-repeat protein 41 contributes to tumour progression in triple-negative breast cancer.

ABSTRACT: WD-repeat proteins are implicated in a variety of biological functions, most recently in oncogenesis. However, the underlying function of WD-repeat protein 41 (WDR41) in tumorigenesis remains elusive. The present study was aimed to explore the role of WDR41 in breast cancer. Combined with Western blotting and immunohistochemistry, the results showed that WDR41 was expressed at low levels in breast cancer, especially in triple-negative breast cancer (TNBC). Using methylation-specific PCR (MSP), we observed that WDR41 presented hypermethylation in MDA-MB-231 cells. Methylation inhibitor 5-aza-2'-deoxycytidine (5-aza-dC) management increased the expression of WDR41 in MDA-MB-231 cells, but not in MCF-10A (normal mammary epithelial cells) or oestrogen receptor-positive MCF-7 breast cancer cells. WDR41-down-regulation promoted, while WDR41-up-regulation inhibited the tumour characteristics of TNBC cells including cell viability, cell cycle and migration. Further, WDR41-up-regulation dramatically suppressed tumour growth in vivo. Mechanistically, WDR41 protein ablation activated, while WDR41-up-regulation repressed the AKT/GSK-3? pathway and the subsequent nuclear activation of ?-catenin in MDA-MB-231 cells, and 5-aza-dC treatment enhanced this effect. After treatment with the AKT inhibitor MK-2206, WDR41-down-regulation-mediated activation of the GSK-3?/?-catenin signalling was robustly abolished. Collectively, methylated WDR41 in MDA-MB-231 cells promotes tumorigenesis through positively regulating the AKT/GSK-3?/?-catenin pathway, thus providing an important foundation for treating TNBC.

SUBMITTER: Wang H

PROVIDER: S-EPMC7299681 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Aberrant methylation of WD-repeat protein 41 contributes to tumour progression in triple-negative breast cancer.

Wang Han H Wu Dan D Cai Liangliang L Li Xiaohong X Zhang Zhiming Z Chen Shuai S

Journal of cellular and molecular medicine 20200512 12

WD-repeat proteins are implicated in a variety of biological functions, most recently in oncogenesis. However, the underlying function of WD-repeat protein 41 (WDR41) in tumorigenesis remains elusive. The present study was aimed to explore the role of WDR41 in breast cancer. Combined with Western blotting and immunohistochemistry, the results showed that WDR41 was expressed at low levels in breast cancer, especially in triple-negative breast cancer (TNBC). Using methylation-specific PCR (MSP), w ...[more]

PMID: 32394588

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Project description:The human DOC-2/DAB2 interactive protein (hDAB2IP) gene is a novel member of the Ras GTPase-activating family and has been demonstrated to be a tumour-suppressor gene inactivated by methylation in several cancers. In this study, we analysed the methylation and expression status of hDAB2IP in gastrointestinal tumours. The promoter region of hDAB2IP was divided into two regions (m2a and m2b) based on our previous report, and the methylation status was determined by bisulphite DNA sequencing in gastric cancer cell lines. The gene expression was semiquantified by real-time RT-PCR, and the results indicated that the m2b promoter region might be an authentic methylation-mediated key regulator of the gene expression. Based on the sequence data, we developed a methylation-specific PCR (MSP) for the m2a and m2b regions and applied it to the samples. Methylation-specific PCR revealed aberrant methylation in the m2a region in eight of 12 gastric cancer cell lines (67%), 16 of 35 gastric cancer tissues (46%) and 29 of 60 colorectal cancer tissues (48%), and in the m2b region in eight of 12 cell lines (67%), 15 of 35 gastric cancer tissues (43%) and 28 of 60 colorectal cancer tissues (47%). On the other hand, seven (12%) and 11 (19%) of 59 gastrointestinal nonmalignant mucosal specimens showed methylation in the m2a and m2b regions, respectively, suggesting that hDAB2IP methylation might play a causative role in carcinogenesis. The 5-aza-2'-deoxycytidine treatment restored the gene expression in the m2b-methylated cell lines, confirming that the methylation caused gene downregulation. We also examined the relationship between hDAB2IP methylation and the clinicopathological features in patients with primary tumours, and determined that methylation in the m2b region was associated with location of the tumour in the stomach. In summary, our results demonstrated that hDAB2IP methylation is frequently present in gastrointestinal tumours and that the resulting gene silencing plays an important role in gastrointestinal carcinogenesis.

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Aberrant methylation of WD-repeat protein 41 contributes to tumour progression in triple-negative breast cancer.

Publications

Aberrant methylation of WD-repeat protein 41 contributes to tumour progression in triple-negative breast cancer.

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